In preliminary work, we have identified a novel class of broad-spectrum antibacterial agents: arylpropionyl phloroglucinols (APPs). APPs potently inhibit bacterial RNA polymerase (RNAP)~but not mammalian RNAP~in vitro, potently inhibit bacterial growth in culture, and potently clear infection in a mouse model of methicillin-resistant Staphylococcus aureus infection. APPs exhibit antibacterial activity against both Gram-positive and Gram-negative bacterial pathogens, including drug-sensitive, beta-lactam-resistant, macrolide-resistant, tetracycline-resistant, rifampin-resistant, vancomycin-resistant, and multi-drug-resistant Staphylococcus aureus, Enterococcus faecalis, NIAID category A pathogen Bacillus anthracis, NIAID category A pathogen Francisella tularensis, and NIAID category B pathogen Brucella melitensis. APPs exhibit no cross-resistance with rifampin, the RNAP inhibitor in current use in broad-spectrum antibacterial therapy, and exhibit a spontaneous resistance rate <1/10 that of rifampin. APP concentrations that inhibit bacteria growth in culture are not cytotoxic to mammalian cells in culture, and APPs do not exhibit acute toxicity in mice upon subcutaneous administration at doses up to 100 mg/kg. We provisionally have defined the binding site on RNAP for APPs and the mechanism of inhibition of RNAP by APPs. The binding site and mechanism have no overlap with the binding site and mechanism ofthe RNAP inhibitor rifampin, consistent with the absence of cross-resistance with rifampin. We have constructed provisional structural models of RNAP-APP complexes, and we have defined provisional structure-activity relationships for APPs. The structural models and structure-activity relationships suggest changes that could be made to APPs to improve potency and properties. APPs can be synthesized in just one or two steps. The simple synthetic procedures enable straightforward preparation of APP analogs. We propose to leverage the structural models, structure-activity relationships, and synthetic procedures from preliminary work in order to design, synthesize, and evaluate APP analogs having increased efficacy.